expert roundtables

Treatment-Resistant Rheumatoid Arthritis: An Unmet Need

by Leonard H. Calabrese, DO; Jeffrey R. Curtis, MD, MS, MPH; and Jonathan Kay, MD


The standards that constitute an acceptable response to therapy are increasingly high. Combination therapy is often required to achieve goals in patients with treatment resistance, but there can be a risk of overtreatment.

Q: What does the future hold for patients with treatment-resistant RA? 

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

“I think that the bar is being set increasingly higher and that we are not looking for minimal responses. In general, we aspire to achieve remission.”

Leonard H. Calabrese, DO

The definition of treatment-resistant rheumatoid arthritis (RA) is an important starting point. Most guidelines uphold that methotrexate (MTX) is the initial drug of choice, and it is important that MTX be given an adequate trial at an appropriate dose. MTX should generally be administered for at least 3 to 4 months, and the upward dose limit is in the range of 15 to 25 mg per week. Another important question is: What constitutes an acceptable response to treatment? I think that the bar is being set increasingly higher and that we are not looking for minimal responses. In general, we aspire to achieve remission. And, given that there is such a robust follow-on pipeline, I think that there are temporal trends for the early addition of a biologic in patients who do not have the desired response. Whether the target is low disease activity or remission, that target must be set as part of a shared and informed decision with the patient. 

With aggressive therapy, there is also the potential for overtreatment, because up to 1 in 3 patients with RA who have joints that are quiet by tender and swollen joint counts still have residual complaints as reflected in their global response. We are talking about controlling the disease at the molecular and cellular levels within the joint and controlling the impact of the disease for the patient (ie, symptom remission). When we consider cases of true primary treatment failure, where the disease never becomes controlled, it is actually a fairly small population of patients. The remainder of those who fail to respond may have persistent pain, fatigue, and/or early morning stiffness, and that is where refined clinical decision making takes place. Thus, when we are trying to help these patients to feel better, I think that we need to recognize those scenarios in which there are no easy medical solutions for quality-of-life improvements.

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

We must differentiate between patients who are experiencing symptoms due to persistent joint inflammation and those whose symptoms are not caused by synovitis.”

Jonathan Kay, MD

I am in complete agreement with Dr Calabrese and would revisit the questions of what treatment-resistant RA actually is and how it is defined. Is it RA with disease activity that persists despite optimization of treatment with currently available agents? Or is it RA in which patients experience symptoms such as pain and stiffness, but not necessarily caused by synovial inflammation? In most clinical trials conducted in RA populations, at least 30% of patients have an inadequate response to MTX. For some, this lack of response may be the result of pain amplification rather than of persistently active synovitis. Thus, we must differentiate between patients who have persistently active disease, despite optimization of all currently available treatments, and those who have a heightened perception of pain that does not respond to antirheumatic drug therapy. 

Now, how does one best assess whether there is persistent disease activity in treatment-resistant patients? Do we use an array of biochemical markers, such as in the multi-biomarker disease activity index? Or do we use magnetic resonance imaging or musculoskeletal ultrasound as an imaging marker to look for abrogation of synovitis? Or do we use some other measure? These are also important questions. In general, I agree that one should first optimize treatment with MTX and then add a biological agent, as early as is feasible. But, to achieve effective results, we must differentiate between patients who are experiencing symptoms due to persistent joint inflammation and those whose symptoms are not caused by synovitis.

Jeffrey R. Curtis, MD, MS, MPH

Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine
Co-Director, UAB Pharmacoepidemiology and Pharmacoeconomics Research (PEER) Unit
Division of Clinical Immunology and Rheumatology
University of Alabama at Birmingham
Birmingham, AL

I think that most people should be encouraged to go on—and stay on—combination therapy, at least earlier in the course of disease, rather than throw in the towel and give up on MTX, often never to return.”

Jeffrey R. Curtis, MD, MS, MPH

I think that we have hit on the key questions, and the other thing I might add is that it seems like there may be somewhat of a backlash against combination therapy, given that many patients do not like to be on MTX. But we should not be pushing monotherapy with a biologic, a Janus kinase inhibitor, or anything else until we have a treatment paradigm where we have got at least 80% or more of our patients who are getting into low disease activity, if not remission. Currently, we are not anywhere close to that with biologic or Janus kinase monotherapy, even for patients with early disease. Further, despite many successful therapies for RA, as recently reported by Winthrop and colleagues, it still seems to be the case that less than half of patients with RA are in remission. I think that most people should be encouraged to go on—and stay on—combination therapy, at least earlier in the course of disease, rather than throwing in the towel and giving up on MTX, often never to return. That is, sometimes there is the risk of being too quick to give up on MTX (or other conventional synthetic disease-modifying antirheumatic drugs) when, in fact, such agents could be used in combination therapy. I agree with Dr Calabrese that the bar is being set higher in that we seek remission, but combination therapy may be needed to achieve that goal. By the time that patients with RA have failed 2 or 3 or 4 biologics, almost half of those individuals are no longer on concomitant MTX, and that, frankly, may not be warranted.


Bécède M, Alasti F, Gessl I, et al. Risk profiling for a refractory course of rheumatoid arthritis. Semin Arthritis Rheum. 2019;49(2):211-217.

Feldman CH, Yoshida K, Xu C, et al. Supplementing claims data with electronic medical records to improve estimation and classification of rheumatoid arthritis disease activity: a machine learning approach. ACR Open Rheumatol. 2019;1(9):552-559.

Kaeley GS, Nishio MJ, Goyal JR, et al. Changes in ultrasonographic vascularity upon initiation of adalimumab combination therapy in rheumatoid arthritis patients with an inadequate response to methotrexate. Arthritis Rheumatol. 2016;68(11):2584-2592.

Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol Int. 2016;36(5):685-695.

Winthrop KL, Weinblatt ME, Bathon J, et al. Unmet need in rheumatology: reports from the Targeted Therapies Meeting 2019. Ann Rheum Dis. 2020;79(1):88-93.

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